Genomic profiling of microphthalmia trios reveals novel pathogenic drivers and repetitive element instability

Abstract

Congenital microphthalmos (CMIC) is a rare ocular malformation with marked genetic heterogeneity. To investigate its genomic landscape, we performed whole-genome sequencing of 10 proband-parent trios and integrated analyses of inherited variants, candidate germline de novo variants, and tandem-repeat variation. Following quality, population-frequency, and de novo probability filtering, 45 candidate germline de novo loci involving 37 genes were prioritized, including variants in POMT1, MYH11, and NR4A1. Rare homozygous variants in ANXA9 and SCARA5 showed recessive segregation in their respective families. Integration of gene-expression profiles and published functional evidence highlighted potential biological links to ocular development, calcium homeostasis, iron transport, and cellular stress responses. Repeat analysis further identified prominent repeat-length outlier signals in probands 5, 9, and 10, including a candidate AACCCT repeat-length alteration overlapping the SOX9/SOX9-AS1 locus in proband 10. Collectively, these findings broaden the spectrum of candidate genomic alterations in CMIC and nominate genes and regulatory loci that may contribute to its molecular pathogenesis. Their specific pathogenic roles and functional effects require further validation in independent cohorts and experimental models.